The overall goals of this project are to quantify dopaminergic innervation changes in the basal ganglia that occur with normal aging or with Parkinson's disease (PD) and to examine the consequences of these changes upon cerebral processes governing motor control. We will measure the pre-synaptic monoaminergic innervation of the striatum and in parallel several behavioral measures of motor performance. We will additionally determine the pattern and magnitude of cerebral blood flow (CBF) activation during a performance-standardized motor task. Positron emission tomography (PET) with (+0[11C]dihydrotetrabenazine will be used to examine the density of pre-synaptic monoaminergic terminals in the striatum and PET with [15O]H2O2 during a motor task involving a manual movement of a joystick will be used to determine cerebral activation as reflected by changes in CBF. Behavioral measures of motor performance will include the Unified Parkinson's Disease Rating Scale (UPDRS) finger tapping rate and grooved pegboard testing. Three specific hypotheses will be tested: (1) the density of striatal monoaminergic pre-synaptic terminals decreases with normal aging, and correspondingly, aspects of motor performance and of cerebral activation with motor tasks decline in the cortical supplementary motor area (SMA); (2) in PD, the decrease in the density of striatal monoaminergic terminals is correlated is correlated with diminished motor performance and with diminished SMA activation; and (3) SMA activation and motor performance deficits attributable to reduced striatal to reduced striatal monoaminergic innervation will be reversible after acute administration of the mixed D1 and D2 receptor agonist apomorphine. The results of these studies will advance our present understanding of the relationships between dopaminergic nigrostriatal pathology and motor performance changes in PD, and provider specific information on the degree to which changes may be attributable to dopamine deficiency alone versus other, secondary mechanisms. Furthermore, testing the possibility that motor performance declines observed in aged subjects without PD may be partially due to striatal dopaminergic denervation will have important implications for possible therapeutic interventions in a large and growing elderly population.
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